1. Field of the Invention
The invention relates generally to the fields of contrast agents for use in imaging and nanoparticles. In certain aspects, gold nanoparticles attached to glucose or a glucose derivative, such as 2-Deoxy-D-Glucose (2-DG), are provided. Such nanoparticles are particularly useful as a contrast agent in imaging, such as computed tomography (CT) or X-ray imaging.
2. Description of Related Art
To accurately stage and treat malignancies, precise knowledge of tumor location, size, and lymphatic or distant spread is essential. In the context of radiation therapy, the advent of highly conformal techniques—such as three-dimensional conformal radiotherapy (3D-CRT), intensity modulated radiotherapy (IMRT) and image guided radiotherapy (IGRT)—has escalated the need for more accurate target visualization and delineation based on anatomic and physiological images. While imaging with computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound imaging (US) provides valuable anatomical information, all lack the high sensitivity and specificity offered by a functional imaging modality such as positron emission tomography (PET) or single photon emission computed tomography (SPECT). However, despite the ability of PET and SPECT to detect functional processes in the body, they suffer from relatively poor spatial resolution compared to many anatomic imaging modalities such as CT. Also, PET imaging has several drawbacks including the production, transportation, and cost of the radiopharmaceuticals, which limit wider use of this technology. Moreover, PET images do not provide anatomical information, and are therefore inadequate for radiation or surgical treatment planning. The recent development of hybrid PET-CT scanners and sophisticated image registration algorithms allows for combined image sets from CT and PET to be used in the diagnosis and staging of malignant diseases. However, despite the benefits of combined PET-CT, the full potential of CT imaging cannot be utilized because the superb spatial resolution provided by CT scans is not shared by the PET images. For instance, current PET technology has limitations in detecting tumors of fewer than 109 cells (approximately 1 cm in diameter) (Weissleder, 2006). That shortcoming has significance for the early diagnosis of cancer, where small malignant lesions can be missed by PET scans.
In the last decade, studies have demonstrated that CT imaging can, when combined with an X-ray contrast agent, offer both anatomical and functional data (Lee, 2002). However, this technique, termed functional CT, has not gained widespread clinical use because of the limitations of current contrast agents. To date, the most commonly used X-ray contrast agents are iodine-based compounds. Despite their clinical use, iodine-based contrast agents have several drawbacks including a high osmolality and a short blood half-life (less than 10 min) that requires imaging immediately after administration. Also, iodine has a moderate atomic number (Z) that limits the level of achievable CT contrast, decreasing its usefulness in radiation therapy planning, which relies almost exclusively on such values. More importantly, commercially available iodine-based X-ray contrast agents lack tumor-specific targeting ability. Conjugates with targeting moieties, such as antibodies, fail to deliver iodine to disease sites at a concentration detectable by current CT scanners. In addition to iodine-based agents, several other experimental X-ray contrast materials have been tested with varying degrees of success (Kao et al., 2003; Schmiedl et al., 1999; Froman et al., 1994); Vera and Mattrey, 2002). However, the development of intravascular X-ray contrast agents based on other mid-Z to high-Z materials, especially those agents with tumor-specific targeting capability, has not been successful due to performance, cost, and toxicity issues (Bonvento et al., 2003; Miyamoto et al., 2006; Yu and Watson, 1999).
Thus, there remains a need for improved contrast agents for use in CT and X-ray imaging, and there is a particular need for contrast agents with tumor-specific targeting ability to serve as a means of functional and/or molecular imaging of cancer. Some studies have investigated the feasibility of using various materials at the nanometer scale (Rabin et al., 2006; Qian et al., 2008; Popvtzer et al., 2008; Cai et al., 2007; Kim et al., 2007; Hainfeld et al., 2006). Gold nanoparticles (AuNPs) may offer advantages over iodine-based compounds. For example, gold attenuates X-rays more effectively than iodine, and thus produces superior contrast. Also, AuNPs may have a longer biological half-life than iodine-based compounds. For these reasons, studies have investigated the use of AuNPs as an X-ray contrast agent, including attempts to target tumor cells using an antibody or other such moiety (Hainfeld et al., 2006; Popvtzer et al., 2008; Gao et al., 2004; Jain et al., 2005; Zhang et al., 2008). Although thioglucose-conjugated AuNPs have been reported as useful for treating cancer (US. Pub. No. 2010/0034735), it remains unknown whether such AuNPs could be used as contrast agents to successfully image tumors using techniques such as CT or X-ray imaging.